Nifedipine disturbs fetal cardiac function during hypoxemia in a chronic sheep model at near term gestation.

BACKGROUND: Nifedipine is a widely used drug in pregnancies complicated by maternal hypertensive disorders that can be associated with placental insufficiency and fetal hypoxemia. The evidence regarding fetal myocardial responses to nifedipine in hypoxemia is limited. OBJECTIVE: We hypothesized that nifedipine would not impair fetal sheep cardiac function under hypoxemic environment. In particular, we investigated the effects of nifedipine on fetal ventricular functional parameters and cardiac output. STUDY DESIGN: A total of 21 chronically instrumented fetal sheep at 122 to 134 gestational days (term, 145 days) were included in this study. Fetal cardiac function was evaluated by measuring global longitudinal strain, indices describing ventricular systolic and diastolic function, and cardiac outputs using two-dimensional speckle tracking and tissue and spectral pulsed-wave Doppler echocardiography. Fetal carotid artery blood pressure and blood gas values were invasively monitored. After baseline data collection, fetal hypoxemia was induced by maternal hyperoxygenation. After hypoxemia phase data collection, 9 fetuses received nifedipine infusion, and 12 fetuses received saline infusion. Data were collected 30 and 120 minutes after the infusion was started. After 120 minutes of data collection, maternal and fetal oxygenation were normalized, and normoxemia phase data were collected, while infusion was continued. RESULTS: Hypoxemia decreased fetal carotid artery mean arterial pressure from 40 (8) mm Hg to 35 (8) mm Hg (P<.007), and left ventricular global longitudinal strain showed less deformation than at baseline (P=.001). Under hypoxemia, nifedipine caused a reduction in right ventricular global longitudinal strain (P<.05), a decrease in right ventricular isovolumic relaxation velocity and its deceleration (P<.01) indicating diastolic dysfunction, and a drop in right ventricular cardiac output (P<.05). Nifedipine did not alter fetal left ventricular functional parameters or cardiac output. When normoxemia was restored, fetal right ventricular functional parameters and cardiac output returned to baseline level. CONCLUSION: In hypoxemic fetus, nifedipine impaired right ventricular function and reduced its cardiac output. The detrimental effects of nifedipine on fetal right ventricular function were abolished, when normoxemia was restored. Our findings suggest that in a hypoxemic environment nifedipine triggers detrimental effects on fetal right ventricular function.

Fetal cardiovascular hemodynamics in type 1 diabetic pregnancies at near-term gestation.

INTRODUCTION: Poor glycemic control in maternal type 1 diabetes mellitus during pregnancy can affect fetal cardiac and placental function. However, studies concerning fetal central hemodynamics have revealed conflicting results. We hypothesized that in pregnancies complicated by maternal type 1 diabetes, fetal cardiovascular and placental hemodynamics are comparable to the control fetuses at near-term gestation. In addition, we investigated the relation between newborn serum biomarkers of cardiac function and fetal cardiovascular and placental hemodynamics. Furthermore, we studied whether maternal diabetes is associated with placental inflammation. MATERIAL AND METHODS: In this prospective case-control study, fetal central and peripheral hemodynamics were assessed by ultrasonography in 33 women with type 1 diabetes and in 67 controls with singleton pregnancies between 34+2 and 40+2 gestational weeks. Newborn umbilical cord serum was collected to analyze cardiac natriuretic peptides (atrial and B-type natriuretic peptides) and troponin T concentrations. Placental tissue samples were obtained for cytokine analyses. RESULTS: Fetal ventricular wall thicknesses were greater and weight-adjusted stroke volumes and cardiac outputs were lower in the type 1 diabetes group than in the control group. Pulsatility in the aortic isthmus and inferior vena cava blood flow velocity waveforms was greater in the type 1 diabetes group fetuses than in the controls. A positive correlation was found between branch pulmonary artery and aortic isthmus pulsatility index values. Umbilical artery pulsatility indices were comparable between the groups. Umbilical cord serum natriuretic peptide and troponin T concentrations were elevated in the type 1 diabetes fetuses. These cardiac biomarkers correlated significantly with cardiovascular hemodynamics. Placental cytokine levels were not different between the groups. CONCLUSIONS: In maternal type 1 diabetes pregnancies, fetal cardiovascular hemodynamics is impaired. Maternal type 1 diabetes does not seem to alter placental vascular impedance or induce placental inflammation.

Foramen ovale blood flow and cardiac function after main pulmonary artery occlusion in fetal sheep.

NEW FINDINGS: What is the central question of this study? At near-term gestation, foramen ovale blood flow accounts for a significant proportion of fetal left ventricular output. Can the foramen ovale increase its volume blood flow when right ventricular afterload is increased by main pulmonary artery occlusion? What is the main finding and its importance? Foramen ovale volume blood flow increased during main pulmonary artery occlusion. However, this increase was attributable to an increase in fetal heart rate, because left ventricular stroke volume remained unchanged. These findings suggest that the foramen ovale has a limited capacity to increase its volume blood flow. ABSTRACT: The foramen ovale (FO) accounts for the majority of fetal left ventricular (LV) output. Increased right ventricular afterload can cause a redistribution of combined cardiac output between the ventricles. To understand the capability of the FO to increase its volume blood flow and thus LV output, we mechanically occluded the main pulmonary artery in seven chronically instrumented near-term sheep fetuses. We hypothesized that FO volume blood flow and LV output would increase during main pulmonary artery occlusion. Fetal cardiac function and haemodynamics were assessed by pulsed and tissue Doppler at baseline, 15 and 60 min after occlusion of the main pulmonary artery and 15 min after occlusion was released. Fetal ascending aorta and central venous pressures and blood gas values were monitored. Main pulmonary artery occlusion initially increased fetal heart rate (P < 0.05) from [mean (SD)] 158 (7) to 188 (23) beats min-1 and LV cardiac output (P < 0.0001) from 629 (198) to 776 (283) ml min-1 . Combined cardiac output fell (P < 0.0001) from 1524 (341) to 720 (273) ml min-1 . During main pulmonary artery occlusion, FO volume blood flow increased (P < 0.001) from 507 (181) to 776 (283) ml min-1 . This increase was related to fetal tachycardia, because LV stroke volume did not change. Fetal ascending aortic blood pressure remained stable. Central venous pressure was higher (P < 0.05) during the occlusion than after it was released. During the occlusion, fetal pH decreased and P C O 2 increased. Left ventricular systolic dysfunction developed while LV diastolic function was preserved. Right ventricular systolic and diastolic function deteriorated after the occlusion. In conclusion, the FO has a limited capacity to increase its volume blood flow at near-term gestation.

The effect of screening-to-labor interval on the sensitivity of late-pregnancy culture in the prediction of group B streptococcus colonization at labor: A prospective multicenter cohort study.

INTRODUCTION: The aim of this study was to evaluate the effect of increasing screening-to-labor interval on the performance of group B streptococcus (GBS) screening by late-pregnancy enriched culture compared with intrapartum real-time polymerase chain reaction (RT-PCR). MATERIAL AND METHODS: Group B streptococcus colonization was determined in 2624 women with singleton pregnancies by culture at 35-37 weeks of gestation and at the beginning of labor by culture and RT-PCR from recto-vaginal swab samples. RESULTS: Group B streptococcus colonization rates were 29.0% in late-pregnancy culture, 29.7% in intrapartum culture and 28.2% in intrapartum PCR. Intrapartum culture was used as a reference, the late-pregnancy culture had an overall sensitivity of 89.2% (95% CI 88.0%-90.4%) and specificity of 96.5% (95% CI 95.8%-97.2%), and intrapartum PCR had sensitivity of 91.5% (95% CI 90.4%-92.6%) and specificity of 98.5% (95% CI 98.0%-99.0%). However, up to 4 weeks after screening, the sensitivity of late-pregnancy culture was equivalent to or higher than that of RT-PCR. The RT-PCR was invalid in 0.9% of the women. Between late-pregnancy screening and labor, GBS colonization changed from negative to positive in 3.2% and from positive to negative in 2.5% of the women. CONCLUSIONS: The late-pregnancy enriched culture and intrapartum RT-PCR have comparable sensitivities in the detection of GBS when culture screening is conducted no more than 4 weeks before labor. Late-pregnancy culture sampling should be postponed to at least 37 weeks of gestation.

Fetal sheep central haemodynamics and cardiac function during occlusion of the ascending aorta.

NEW FINDINGS: What is the central question of this study? The fetal aortic isthmus has an important physiological role, allowing communication between the left and right ventricular outputs, which are arranged in parallel. Can the aortic isthmus provide unrestrictive communication between the left and right ventricular circulations during occlusion of the ascending aorta? What is the main finding and its importance? During occlusion of the ascending aorta, fetal carotid artery perfusion pressure fell significantly, showing that the aortic isthmus failed to redirect blood flow and pressure from the ductus arteriosus to the aortic arch. This suggests that the aortic isthmus cannot provide unrestrictive communication between left and right ventricular circulations. The fetal aortic isthmus (AoI) allows communication between left (LV) and right ventricular (RV) outputs and represents an arterial watershed between the brachiocephalic (brain) and subdiaphragmatic (placenta) circulations. To understand the capability of the AoI to maintain the balance between the upper and lower body circulations, we performed a complete occlusion of the fetal ascending aorta in nine chronically instrumented sheep at near term gestation. We hypothesized that the occlusion would significantly decrease LV output and concomitantly increase RV output in order to maintain adequate systemic cardiac output and perfusion pressure to the fetal brain circulation through retrograde filling of the AoI. Fetal cardiac function and haemodynamics were assessed by pulsed and tissue Doppler at baseline, 15 and 60 min after occlusion of the ascending aorta and 15 min after occlusion was released. Carotid artery and jugular vein pressures were monitored. Occlusion of the ascending aorta increased (P < 0.002) RV output from [mean (SD)] 684 (369) to 907 (414) ml min-1 and decreased (P < 0.0001) LV output from 440 (136) to 40 (16) ml min-1 . Combined cardiac output decreased (P < 0.02) from 1125 (494) to 946 (417) ml min-1 . During occlusion, carotid artery mean pressure decreased from 32 (7) to 12 (7) mmHg (P < 0.0001). Systemic venous pressure was unaffected. Left ventricular systolic and diastolic function deteriorated during occlusion. Right ventricular systolic function improved, while diastolic dysfunction developed. Fetal carotid artery perfusion pressure decreased significantly during occlusion of the ascending aorta, demonstrating that AoI failed to redirect blood flow and pressure from the ductus arteriosus to the aortic arch. Our finding suggests that at near term gestation the aortic AoI cannot provide unrestrictive communication between LV and RV circulations.

Maternal hyperglycemia leads to fetal cardiac hyperplasia and dysfunction in a rat model.

Accelerated fetal myocardial growth with altered cardiac function is a well-documented complication of human diabetic pregnancy, but its pathophysiology is still largely unknown. Our aim was to explore the mechanisms of fetal cardiac remodeling and cardiovascular hemodynamics in a rat model of maternal pregestational streptozotocin-induced hyperglycemia. The hyperglycemic group comprised 107 fetuses (10 dams) and the control group 219 fetuses (20 dams). Fetal cardiac function was assessed serially by Doppler ultrasonography. Fetal cardiac to thoracic area ratio, newborn heart weight, myocardial cell proliferative and apoptotic activities, and cardiac gene expression patterns were determined. Maternal hyperglycemia was associated with increased cardiac size, proliferative, apoptotic and mitotic activities, upregulation of genes encoding A- and B-type natriuretic peptides, myosin heavy chain types 2 and 3, uncoupling proteins 2 and 3, and the angiogenetic tumor necrosis factor receptor superfamily member 12A. The genes encoding Kv channel-interacting protein 2, a regulator of electrical cardiac phenotype, and the insulin-regulated glucose transporter 4 were downregulated. The heart rate was lower in fetuses of hyperglycemic dams. At 13-14 gestational days, 98% of fetuses of hyperglycemic dams had holosystolic atrioventricular valve regurgitation and decreased outflow mean velocity, indicating diminished cardiac output. Maternal hyperglycemia may lead to accelerated fetal myocardial growth by cardiomyocyte hyperplasia. In fetuses of hyperglycemic dams, expression of key genes that control and regulate cardiomyocyte electrophysiological properties, contractility, and metabolism are altered and may lead to major functional and clinical implications on the fetal heart.

Peripheral chemoreflex activation and cardiac function during hypoxemia in near-term fetal sheep without placental compromise.

A drop in arterial oxygen content activates fetal chemoreflex including an increase in sympathetic activity leading to peripheral vasoconstriction and redistribution of blood flow to protect the brain, myocardium, and adrenal glands. By using a chronically instrumented fetal sheep model with intact placental circulation at near-term gestation, we investigated the relationship between peripheral chemoreflex activation induced by hypoxemia and central hemodynamics. A total of 17 Åland landrace sheep fetuses at 115-128/145 gestational days were instrumented. Carotid artery was catheterized in 10 fetuses and descending aorta in 7 fetuses. After a 4-day recovery, baseline measurements of fetal arterial blood pressures, blood gas values, and fetal cardiovascular hemodynamics by pulsed Doppler ultrasonography were obtained under isoflurane anesthesia. Comparable data to baseline were collected 10 min (acute hypoxemia) and 60 min (prolonged hypoxemia) after maternal hypo-oxygenation to saturation level of 70%-80% was achieved. During prolonged hypoxemia, pH and base excess (BE) were lower and lactate levels were higher in the descending aorta than in the carotid artery. During hypoxemia mean arterial blood pressure (MAP) in the descending aorta increased, whereas in the carotid artery, MAP decreased. In addition, right pulmonary artery pulsatility index values increased, and the diastolic component in the aortic isthmus blood flow velocity waveform became more retrograde, thus decreasing the aortic isthmus antegrade/retrograde blood flow (AoI Net Flow) ratio. Both fetal ventricular cardiac outputs were maintained even during prolonged hypoxemia when significant fetal metabolic acidemia developed. Fetal chemoreflex activation induced by hypoxemia decreased the perfusion pressure in the cerebral circulation. Fetal weight-indexed left ventricular cardiac output (LVCO) or AoI Net Flow ratio did not correlate with a drop in carotid artery blood pressure.NEW & NOTEWORTHY During fetal hypoxemia with intact placental circulation, peripheral chemoreflex was activated, as demonstrated by an increase in the descending aorta blood pressure, pulmonary vasoconstriction, and an increase in retrograde diastolic AoI blood flow, while both ventricular cardiac outputs remained stable. However, perfusion pressure in the cerebral circulation decreased. These changes were seen even during prolonged hypoxemia when significant metabolic acidosis developed. Weight-indexed LVCO or AoI Net Flow ratio did not correlate with a drop in carotid artery blood pressure.

Ductus venosus velocimetry in acute fetal acidemia and impending fetal death in a sheep model of increased placental vascular resistance.

We investigated whether hypoxemia without acidemia affects ductus venosus (DV) blood velocity waveform pattern in sheep fetuses with intact placenta and whether worsening acidemia and impending fetal death are related to changes in DV velocimetry in fetuses with increased placental vascular resistance. A total of 34 fetuses were instrumented at 115-136/145 days of gestation. Placental embolization was performed in 22 fetuses on the fourth postoperative day, 24 h before the experiment. The control group was comprised of 12 fetuses with intact placenta. The experimental protocol consisted of fetal hypoxemia that was induced by replacing maternal inhaled oxygen with medical air. To further deteriorate fetal oxygenation and blood-gas status, uterine artery volume blood flow was reduced by maternal hypotension. Fetuses that underwent placental embolization were divided into two groups according to fetal outcome. Group 1 consisted of 12 fetuses that completed the experiment, and group 2 comprised 10 fetuses that died during the experiment. DV pulsatility index for veins (PIV) and fetal cardiac outputs (COs) were calculated. Placental volume blood flow, fetal blood pressures, and acid base and lactate values were monitored invasively. On the experimental day, the mean gestational age did not differ significantly between the groups. In groups 1 and 2, the baseline mean DV PIV and fetal COs were not statistically significantly different from the control group. In the control group, the DV PIV values increased significantly with hypoxemia. In groups 1 and 2, the DV PIV values did not change significantly, even with worsening acidemia and imminent fetal death in group 2. During the experiment, the fetal COs remained unchanged. We conclude that fetal hypoxemia increases the pulsatility of DV blood velocity waveform pattern. In fetuses with elevated placental vascular resistance, DV pulsatility does not increase further in the presence of severe and worsening fetal acidemia and impending fetal death.

Low-dose aspirin therapy and hypertensive pregnancy complications in unselected IVF and ICSI patients: a randomized, placebo-controlled, double-blind study.

BACKGROUND: Low-dose aspirin therapy could improve remodelling of maternal spiral arteries during early placentation and prevent subsequent pregnancy-related hypertensive disorders. We investigated whether low-dose aspirin therapy reduces the incidence of hypertensive pregnancy complications in unselected IVF and ICSI patients when medication was started prior to pregnancy. METHODS: A total of 487 patients who underwent IVF/ICSI were randomized to receive 100 mg aspirin (n = 242) or placebo (n = 245) daily, starting on the first day of gonadotrophin stimulation. Pregnant women continued the medication until delivery. A total of 107 patients (52 with aspirin and 55 with placebo) experienced live birth and were included in this follow-up study. The main outcome measure was the incidence of hypertensive pregnancy complications. RESULTS: Embryo transfer took place in 227 (94%) women in the aspirin group and in 229 (93%) women in the placebo group. The live birth rate between the aspirin (22.9%) and placebo (24.0%) groups did not differ significantly (P = 0.78). The overall incidence of hypertensive pregnancy complications was 15.4% (8/52) in the aspirin group and 18.2% (10/55) in the placebo group (P = 0.70, 95% confidence interval for the difference of proportions -17 to 11%). There were two cases of severe pre-eclampsia in the aspirin group and three cases in the placebo group. CONCLUSIONS: In the present study, the incidence of hypertensive pregnancy complications did not differ statistically significantly between low-dose aspirin and placebo groups in unselected IVF/ICSI patients, when medication was started concomitantly with gonadotrophin stimulation and continued until delivery. The study was registered at clinicaltrials.gov. NCT00683202.

Effects of nifedipine and sildenafil on placental hemodynamics and gas exchange during fetal hypoxemia in a chronic sheep model.

INTRODUCTION: We hypothesized that nifedipine and sildenafil would have no detrimental effects on placental hemodynamics and gas exchange under fetal hypoxemia. METHODS: In 33 chronically instrumented fetal sheep, placental volume blood flow (QPlac) and umbilical artery (UA) vascular impedance were measured by Doppler ultrasonography. Fetal carotid artery blood pressure and blood gas values were monitored. After baseline data collection, maternal and fetal hypoxemia were induced. Following hypoxemia phase data collection, 12 fetuses received sildenafil and 9 fetuses nifedipine infusion, and 12 fetuses served as controls receiving saline infusion. Data were collected 30 and 120 min after infusion was started. Then maternal oxygenation was normalized and normoxemia phase data were collected, while infusion was continued. RESULTS: Hypoxemia significantly decreased fetal pO2 and blood pressure. In the sildenafil group at 30- and 120-min hypoxemia + infusion phases, fetal blood pressure and QPlac were significantly lower and pCO2 higher than at baseline without returning to baseline level at normoxemia + infusion phase. In hypoxemia, nifedipine did not affect fetal blood pressure or placental hemodynamics. Both in the sildenafil and nifedipine groups, fetal pO2 remained significantly lower at normoxemia + infusion phase than in the control group. Umbilical artery vascular impedance did not change during the experiment. DISCUSSION: In fetal hypoxemia, sildenafil had detrimental effects on placental hemodynamics that disturbed placental gas exchange. Nifedipine did not alter placental hemodynamics in hypoxemia but disturbed placental gas exchange upon returning to normoxemia. Umbilical artery vascular impedance did not reflect alterations in placental hemodynamics.

Low-dose aspirin and uterine haemodynamics on the day of embryo transfer in women undergoing IVF/ICSI: a randomized, placebo-controlled, double-blind study.

BACKGROUND: Increased uterine artery (UtA) vascular impedance at the time of embryo transfer can decrease implantation and pregnancy rates in women undergoing IVF/ICSI. We hypothesized that low-dose aspirin decreases UtA vascular impedance on the day of embryo transfer in unselected IVF/ICSI patients when medication is started concomitantly with controlled ovarian stimulation. In addition, as secondary outcome measures, we investigated whether low-dose aspirin decreases the incidence of non-optimal (bilateral UtA PI > or = 3.0) uterine haemodynamics and whether it affects arcuate, radial and spiral artery vascular impedances and endometrial thickness. METHODS: A total of 122 women who underwent IVF/ICSI were randomized to receive 100 mg aspirin (n = 61) or placebo (n = 61) daily, starting on the first day of gonadotrophin stimulation. Doppler ultrasonography was performed on the day of embryo transfer. RESULTS: Embryo transfer took place in 57 women in the aspirin group and in 56 women in the placebo group. UtA mean PI values did not differ significantly between the groups. The incidence of non-optimal uterine haemodynamics was lower in the aspirin group than in the placebo group (P = 0.03). Other secondary outcome measures did not differ between the groups. CONCLUSIONS: In unselected IVF/ICSI women, low-dose aspirin therapy, when started concomitantly with controlled ovarian stimulation, did not affect UtA vascular impedance on the day of embryo transfer. However, the incidence of non-optimal uterine haemodynamics was significantly lower in the aspirin group than in the placebo group. ClinicalTrials.gov: NCT00683202.

Effect of Sildenafil on Pulmonary Circulation and Cardiovascular Function in Near-Term Fetal Sheep During Hypoxemia.

Sildenafil is a potential new treatment for placental insufficiency in human pregnancies as it reduces the breakdown of vasodilator nitric oxide. Pulmonary vasodilatation is observed in normoxemic fetuses following sildenafil administration. Placental insufficiency often leads to fetal hypoxemia that can cause pulmonary vasoconstriction and fetal cardiac dysfunction as evidenced by reduced isovolumic myocardial velocities. We tested the hypotheses that sildenafil, when given directly to the hypoxemic fetus, reverses reactive pulmonary vasoconstriction, increases left ventricular cardiac output by increasing pulmonary venous return, and ameliorates hypoxemic myocardial dysfunction. We used an instrumented sheep model. Fetuses were made hypoxemic over a mean (standard deviation) duration of 41.3 (9.5) minutes and then given intravenous sildenafil or saline infusion. Volume blood flow through ductus arteriosus was measured with an ultrasonic transit-time flow probe. Fetal left and right ventricular outputs and lung volume blood flow were calculated, and ventricular function was examined using echocardiography. Lung volume blood flow decreased and the ductus arteriosus volume blood flow increased with hypoxemia. There was a significant reduction in left ventricular and combined cardiac outputs during hypoxemia in both groups. Hypoxemia led to a reduction in myocardial isovolumic velocities, increased ductus venosus pulsatility, and reduced left ventricular myocardial deformation. Direct administration of sildenafil to hypoxemic fetus did not reverse the redistribution of cardiac output. Furthermore, fetal cardiac systolic and diastolic dysfunction was observed during hypoxemia, which was not improved by fetal sildenafil treatment. In conclusion, sildenafil did not improve pulmonary blood flow or cardiac function in hypoxemic sheep fetuses.

Interobserver agreement in the assessment of intrapartum automated fetal electrocardiography in singleton pregnancies.

OBJECTIVE: To study interobserver agreement in the assessment of intrapartum automated fetal electrocardiogram ST interval analysis (STAN). DESIGN: Observational study. SETTING: Labor ward in tertiary level university hospital. Sample. Two hundred (140 reassuring and 60 non-reassuring) STAN recordings on non-selected women with singleton, vertex, term pregnancies were selected from our archive. Samples of 60-min were analysed from the end of each recording, excluding the last 30 min before delivery. METHODS: Three consultants, who had undergone STAN training and had clinical experience in using STAN, reviewed the recordings using cardiotocography (CTG) and ST information with no clinical data. The reviewers were asked to follow STAN guidelines and 1 to classify the CTG as normal, intermediary, abnormal, or preterminal, and 2 to make a clinical decision on labor management. MAIN OUTCOME MEASURES: Interobserver agreement evaluated by weighted kappa (kappa(w)) values and the proportion of agreement. RESULTS: In CTG classification, the interobserver agreement between three observers was moderate (kappa(w), 0.47-0.48). The proportion of agreement was 56-59%. In clinical decision-making, kappa(w) values varied from 0.47 to 0.60, and the proportion of agreement was 80-86%. CONCLUSIONS: In non-selected term pregnancies, the interobserver agreement among experienced obstetricians in the classification of CTG and clinical decision-making according to STAN guidelines is moderate at best.

Effect of Hypoxemia on Fetal Ventricular Deformation in a Chronically Instrumented Sheep Model.

We hypothesized that in near-term sheep fetuses, hypoxemia changes myocardial function as reflected in altered ventricular deformation on speckle-tracking echocardiography. Fetuses in 21 pregnant sheep were instrumented. After 4 d of recovery, fetal cardiac function was assessed by echocardiography at baseline, after 30 and 120 min of induced fetal hypoxemia and after its reversal. Left (LV) and right (RV) ventricular cardiac output and myocardial strain were measured. Baseline mean (standard deviation [SD]) LV and RV global longitudinal strains were -18.7% (3.8) and -14.3% (5.3). Baseline RV global longitudinal and circumferential deformations were less compared with those of the left ventricle (p = 0.016 and p < 0.005). LV, but not RV, global longitudinal strain was decreased (p = 0.003) compared with baseline with hypoxemia. Circumferential and radial strains did not exhibit significant changes. In the near-term sheep fetus, LV global longitudinal and circumferential strains are more negative than RV strains. Acute hypoxemia leads to LV rather than RV dysfunction as reflected by decreased deformation.

Effect of Hypoxemia with or without Increased Placental Vascular Resistance on Fetal Left and Right Ventricular Myocardial Performance Index in Chronically Instrumented Sheep.

Myocardial performance index (MPI) is increased in growth-restricted fetuses with placental insufficiency, but it is unknown if this is due to fetal hypoxemia or increased placental vascular resistance (Rplac). We used chronically instrumented sheep fetuses (n = 24). In 12 fetuses, placental embolization was performed 24 h before experiments. On the day of the experiment, left (LV) and right (RV) ventricular MPIs were obtained by pulsed Doppler at baseline and in the hypoxemia and recovery phases. At baseline, Rplac was greater and fetal pO2 lower in the placental embolization group, but RV and LV MPIs were comparable to those of the control group. During hypoxemia, mean LV MPI increased significantly only in fetuses with an intact placenta (0.34 vs. 0.46), returning to baseline during the recovery phase. Right ventricular MPI was unaffected. We conclude that fetal LV function is sensitive to acute hypoxemia. Exposure to chronic hypoxemia could pre-condition the fetal heart and protect its function with worsening hypoxemia.

Fentanyl Pharmacokinetics in Pregnant Sheep after Intravenous and Transdermal Administration to the Ewe.

Fentanyl is used for pain treatment during pregnancy in human beings and animals. However, fentanyl pharmacokinetics during pregnancy has not been fully established. The aim of this study was to characterize fentanyl pharmacokinetics in pregnant sheep after intravenous and transdermal dosing during surgical procedure performed to ewe and foetus. Pharmacokinetic parameters reported for non-pregnant sheep and nominal transdermal dose rate were utilized for a priori calculation to achieve analgesic fentanyl concentration (0.5-2 ng/ml) in maternal plasma. A total of 20 Aland landrace ewes at 118-127 gestational days were used. In the first protocol, 1 week before surgery, 10 animals received 2 µg/kg fentanyl intravenous bolus, and on the operation day, transdermal fentanyl patches at nominal dose rate of 2 µg/kg/hr were applied to antebrachium, and ewes were then given a 2 µg/kg intravenous bolus followed by an intra-operative 2.5 µg/kg/hr infusion. In the second protocol, 10 animals received fentanyl only as transdermal patches on the operation day and oxycodone for rescue analgesia. The data were analysed with population pharmacokinetic modelling. Intra- and post-operative fentanyl concentrations were similar and slightly lower than the a priori predictions, and elimination and distribution clearances appeared slower during than before or after the surgery. Transdermal patches provided sustained fentanyl absorption for up to 5 days, but the absorption rate was slower than the nominal dose rate and showed a high interindividual variability. Further research is warranted to evaluate the clinical relevance of the observations made in sheep.

Fetal sheep left ventricle is more sensitive than right ventricle to progressively worsening hypoxemia and acidemia.

OBJECTIVE: In a sheep model we tested the hypothesis that the fetal left ventricle is less tolerant to worsening acidemia than the right ventricle. STUDY DESIGN: At 106-124/145 days of gestation, 12 fetuses were instrumented. After a 4-day recovery, placental vascular resistance was increased by fetal angiotensin (AT) II infusion. After a 2h ATII infusion, to further deteriorate fetal oxygenation, maternal hypoxemia was induced. Fetal cardiac function and hemodynamics were assessed by tissue Doppler imaging (TDI) and pulsed Doppler imaging. Ultrasonography was performed at baseline, at 1 and 2h after the beginning of ATII infusion and during the ATII+hypoxemia phase. RESULTS: Fetal pH and pO2 decreased significantly and progressively during the experiment. Left ventricular TDI-derived isovolumic relaxation velocity (IVRV) was lower during ATII 2h and ATII+hypoxemia phases than at baseline. The IVRV deceleration was significantly less during the ATII+hypoxemia phase than at baseline. Right ventricular IVRV was significantly lower during the ATII+hypoxemia phase than at baseline. IVRV deceleration did not change. Only left ventricular IVRV deceleration correlated with fetal pO2 (R=0.36, p<0.05). Fetal right and left ventricular cardiac outputs, as well as umbilical artery, aortic isthmus and ductus venosus pulsatility indices remained unchanged during the experiment. CONCLUSION: Our results show that signs of cardiac dysfunction develop earlier in the left ventricle than in the right ventricle. The fetal left ventricle seems to be more sensitive to progressively worsening hypoxemia and acidemia than the right ventricle.

Fetal cardiac function after labetalol or pindolol for maternal hypertension in a sheep model of increased placental vascular resistance.

OBJECTIVE: We hypothesized that labetalol and pindolol have no detrimental effects on fetal cardiac function and pulmonary hemodynamics when administered for norepinephrine-induced maternal hypertension in a chronic sheep model of increased placental vascular resistance. Specifically, we investigated the effects of labetalol and pindolol on fetal cardiopulmonary responses to acute hypoxemia. STUDY DESIGN: Twenty chronically instrumented near-term ewes with increased placental vascular resistance after placental embolization were anesthetized and randomized to receive labetalol or pindolol for norepinephrine-induced hypertension. Thereafter, maternal inspiratory oxygen fraction was decreased to induce fetal hypoxemia. At the end of each phase, fetal hemodynamics were assessed by Doppler ultrasonography. The data were analyzed using repeated measures ANOVA. RESULTS: Maternal administration of norepinephrine had no effect on fetal hemodynamics. Pindolol decreased fetal heart rate and weight-indexed left ventricular cardiac output and increased pulmonary vascular impedances, while labetalol had no effect on these parameters. During hypoxemia, fetal heart rate increased to baseline in the pindolol group and pulmonary vascular impedances increased in the labetalol group, with no changes in fetal cardiac outputs. CONCLUSION: Pindolol decreased fetal left ventricular cardiac output and induced vasoconstriction in the pulmonary vasculature, but neither pindolol nor labetalol significantly modified fetal cardiopulmonary responses to acute hypoxemia.

Effect of angiotensin II on the left ventricular function in a near-term fetal sheep with metabolic acidemia.

We tested the hypothesis that, in acute metabolic acidemia, the fetal left ventricle (LV) has the capacity to increase its contractility in response to angiotensin II infusion. Eleven ewes and their fetuses were instrumented at 127-138/145 days of gestation. The effect of angiotensin II on fetal LV function was assessed using intraventricular pressure catheter and tissue Doppler imaging (TDI). Angiotensin II increased fetal arterial blood pressure, whereas pH and pO(2) decreased. The heart rate and systemic venous pressure were not affected significantly. The LV end-diastolic and end-systolic pressures, as well as dP/dt(max), increased. The TDI-derived LV longitudinal myocardial isovolumic contraction velocity and its acceleration and velocity during early filling were higher than those at baseline. The incidence of absent isovolumic relaxation velocity was greater during angiotensin II infusion. In summary, during acute metabolic acidemia, the fetal left ventricle could increase its contractility in response to inotropic stimulus even in the presence of increased afterload. The diastolic LV function parameters were altered by angiotensin II.

Placental and fetal hemodynamics after labetalol or pindolol in a sheep model of increased placental vascular resistance and maternal hypertension.

We investigated the effects of labetalol and pindolol on uterine, placental, and fetal hemodynamics following norepinephrine-induced maternal hypertension in a sheep model of increased placental vascular resistance. Also, we examined fetal and placental hemodynamic responses to acute hypoxemia after antihypertensive medication. Norepinephrine increased maternal heart rate (HR), mean arterial pressure (MAP) and uterine vascular resistance (R(UtA)), and decreased uterine volume blood flow (Q(UtA)). Both labetalol and pindolol decreased maternal HR, MAP, and R(UtA), but did not restore Q(UtA). Fetal MAP was unaffected while fetal HR and placental volume blood flow (Q(UA)) decreased and placental vascular resistance increased. During hypoxemia, which was induced by decreasing maternal inspiratory oxygen fraction, all these parameters remained unchanged in the labetalol group while fetal HR increased and Q(UA) further decreased in the pindolol group. We conclude that labetalol and pindolol may compromise uterine and placental hemodynamics. Hypoxemic stress provokes divergent hemodynamic responses in fetuses exposed to these differently acting adrenoceptor antagonists.